This invention is related to a method and compound for treating CNS disorders and/or improving cognitive ability in a mammal.
Considerable attention has been directed at methods for treating CNS diseases including those disorders which are influenced by changes in excitatory amino acid transmission. These diseases include senile dementia of the Alzheimer's type (SDAT), age-associated memory impairment, Parkinson's Disease, Huntington's Chorea, major affective disorders, neurotic and psychotic disorders, stroke, ischemia and other neurodegenerative disorders. Of particular importance is the treatment of age-related memory impairment, including Alzheimer's disease. As the population has aged, compounds and methods of treatment of this cognitive impairment have increased in importance. It has been estimated that the incidence of Alzheimer's disease increases from 1 to 47% over a twenty year period starting at age 65.
Felbamate, 2-phenyl-1,3 propanediol dicarbamate, has been found to be an effective anticonvulsant agent. Tetrahedron Vol. 42, No. 23 pp. 6399-6404 (1986) reports that three major metabolites of felbamate have been identified, including 2-phenyl-1,3-propanediol monocarbamate. This publication also discloses a method of preparing this metabolite. However, this reference does not disclose any utility for this metabolite.
European Patent Publication No. 0 531 105 A1 discloses the use of felbamate for treating and controlling the symptoms of, or for the prevention and control of neurodegenerative disorders associated with the loss of cognitive performance resulting from the loss of cholinergic neurons and/or excessive activation of the N-methyl-D-aspartate (NMDA) receptor complex in human or other warm blooded animals. This European publication discloses the utility of this compound for cognitive deficits of the type produced by Alzheimer's or age-related dementia. This European publication also reports that felbamate may be useful in treatment of disorders such as, for example, hypoxia either alone, e.g. by CO poisoning, near drowning; or combined with ischemic blood flow reduction, e.g. cardiac arrest; stroke; anxiety and neurodegenerative diseases, e.g. Guam ALS, Parkinson's disease, Alzheimer's disease, dementia and lathrism. This publication also discloses the use of 2-phenyl-1,3-propanediol for the manufacture of a medicament for treating and controlling the symptoms of, or for the prevention and control of neurodegenerative disorders associated with or resulting from the loss of cholinergic neurons and/or excessive activation of the NMDA receptor complex in human or other warm blooded mammals. This publication does not present any data to support the conclusion that there is an increase or decrease in activation of NMDA receptors in Alzheimer's disease.
Drugs of the Future, Vol 11, No. 11, pp. 931-932 (1986) reports that a minor metabolite of felbamate is 2-phenyl-1,3-propanediol monocarbamate. No utility is suggested for this metabolite.
It has now been found that the compound 2-phenyl-1,3-propanediol monocarbamate functions as a unique cognitive enhancer and may be effective in the treatment of the various CNS disorders previously noted, including Alzheimer's disease. This compound enhances cognitive abilities by reversing deficits resulting from a loss of cholinergic or NMDA receptor function. Its action is uniquely different from felbamate.
Accordingly, it would be desirable to provide a method of treating CNS disorders in mammals, particularly age-associated memory impairment.
It also would be advantageous to provide a compound and pharmaceutical formulation effective in modulating cognition which will cross the blood-brain barrier and enhance cognition function over a wide dosage range.